Vagus Nerve Stimulation: A Bioengineering Approach to Assess its Effects on Resetting the Epileptic Brain Dynamics Epilepsy is the second most common neurological disorder to stroke and affects 1% to 2% of the population worldwide. The Vagus Nerve Stimulation (VNS) is a recent, FDA approved, therapy for epilepsy. Although VNS is a form of neuromodulation, and a promising therapy for epilepsy and other neurological disorders (e.g. depression, bipolar disorder, anxiety), its mechanism of action on reducing the seizure frequency and severity in patients with refractory epilepsy remains unknown. Our research on the dynamical analysis of the scalp and depth EEG, in both animal models and human subjects with epilepsy, has shown that a) seizures are preceded by a pathological, progressive synchronization of nonfocal ("normal") brain sites with the epileptogenic focus long (average of 70 minutes) prior to a seizure onset, and b) this preictal synchronization is reversed postictally via what we have called resetting of the brain dynamics. In 2003, this line of research led to the development of the first prospective on-line real-time seizure prediction algorithm (Iasemidis and colleagues). Prediction paves the way to control. Seizure control experiments were initiated, first in biologically plausible computer models that exhibit "seizures", and subsequently in rodent models of epilepsy. These experiments pointed out to the same direction: pathological seizure precursors similar to the ones in human EEG were found in both the computer and animal models, intervention via timely electrical stimuli reset these precursors and reduced the probability of occurrence of seizures. Encouraged by these results, we herein propose a proof-of-concept study on seizure control in humans. We will seek to relate the successes and failures of the VNS treatment of patients to the VNS capability of resetting or not resetting the pathology in epileptic brain dynamics respectively. Our central hypothesis is that VNS would be a successful therapeutic modality for a patient if it resets the existing pathology of brain dynamics. We expect that a longitudinal dynamical analysis of the scalp EEG recorded from patients with implanted VNS devices will shed light on the investigation of this hypothesis. The EEG from patients at Barrow Neurological Institute will be monitored at regular visits over a period of 2 years after implantation of their VNS devices, that is the period over which successful VNS treatment achieves its most dramatic effect, slowly saturating thereafter. The participating physicians will be blinded to the results of the dynamical EEG analysis, thus avoiding any crossovers between this study and the medical care of the patients. This exploratory research is designed to provide preliminary data about the mechanism of VNS action on the basis of brain dynamics, the plasticity of VNS and brain's macroscopic electrical dynamics, and insights into improving VNS efficacy (e.g. by selection of electrical stimulation parameters that most effectively reset the pathological brain dynamics). The proposed research is an interdisciplinary investigation within the disciplines of bioengineering, neuroscience, neurology and neurosurgery towards the development of intelligent brain stimulators for epilepsy and other neurological disorders. PUBLIC HEALTH RELEVANCE: Vagus Nerve Stimulation: A Bioengineering Approach to Assess its Effects on Resetting the Epileptic Brain Dynamics We propose a 2-year longitudinal dynamical analysis of electroencephalograms (EEGs), recorded from patients with focal epilepsy and implanted Vagus Nerve Stimulation (VNS) devices, that will correlate evoked changes by VNS on their brain dynamics (i.e. brain resetting) with corresponding changes in their seizure frequency and seizure severity. This exploratory interdisciplinary research will provide initial clues about the mechanism of action of VNS, as well as further insight into how to modify the VNS stimulation parameters in order to maximize its efficacy for epilepsy, and possibly for other neurological disorders (e.g. depression, bipolar disorder, and anxiety), in the near future.